ClinVar Miner

Submissions for variant NM_000038.6(APC):c.904C>T (p.Arg302Ter) (rs137854568)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164370 SCV000215005 pathogenic Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing The p.R302* pathogenic mutation (also known as c.904C>T), located in coding exon 8 of the APC gene, results from a C to T substitution at nucleotide position 904. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has previously been reported in multiple individuals with attenuated or classic familial adenomatous polyposis (FAP) (Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Nishisho I et al. Science. 1991 Aug;253:665-9; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J Mol Diagn. 2013 Jan;15(1):31-43). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210154 SCV000266010 pathogenic Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000000834 SCV000282851 pathogenic Familial adenomatous polyposis 1 2020-02-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg302*) in the APC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with familial adenomatous polyposis, Gardner syndrome, and colorectal cancer (PMID: 1651563, 11317365, 16317745, 20685668, 23159591, 23561487). ClinVar contains an entry for this variant (Variation ID: 798). Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000077996 SCV000680600 pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted APC c.904C>T at the cDNA level and p.Arg302Ter (R302X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals and kindreds with Familial Adenomatous Polyposis (Nishisho 1991, Aceto 2005, Garcia-Lozano 2005, Rivera 2011, Kerr 2013, Torrezan 2013) and is considered pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000499742 SCV000781068 pathogenic Familial multiple polyposis syndrome 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000000834 SCV000838072 pathogenic Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077996 SCV000887556 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164370 SCV000905877 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000499742 SCV001361364 pathogenic Familial multiple polyposis syndrome 2019-04-18 criteria provided, single submitter clinical testing Variant summary: APC c.904C>T (p.Arg302X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1690C>T, p.Arg564X; c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; c.3340C>T, p.Arg1114X). The variant was absent in 251112 control chromosomes (gnomAD). The variant, c.904C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Friedl_2005, Rivera_2010, Lin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000834 SCV000020980 pathogenic Familial adenomatous polyposis 1 2013-04-04 no assertion criteria provided literature only
OMIM RCV000000835 SCV000020985 pathogenic Gardner syndrome 2006-11-30 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000077996 SCV000257037 pathogenic not provided no assertion criteria provided research
Division of Human Genetics,Children's Hospital of Philadelphia RCV000000834 SCV000536922 pathogenic Familial adenomatous polyposis 1 2016-06-11 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077996 SCV000591059 uncertain significance not provided no assertion criteria provided clinical testing

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